2-phenacylpyrimidines and method of preparing the same



Patented Nov. 8, 1949 UNITED James Smith. .:Jr'.,.Nortl1'P .bara Roth, Middlesex, N. J;.,'as n .can Q anem d Q Y New Y "corporation of Maine minimisation AND METHOD oF PREPARING THE SAME No Drawing. Application lvlarch lhl ls,

Serial No. 14 386 10 Claims. (01. eta-231) mula:

is a monocyiclicarylradical and R which is..a--2"-pyrimidyl radical which may bear additionalsubstituents.

' The compounds are generally characterizedas beingQcrystalline, .white toflpale .yellow solids, solble-.in most organicsolvents suchv as benzene,

diethyl ether, isopro'pylacetate, glacial acetic acid and the like, butibeing substantially insoljible in water. Some of the compounds, are .of value .for. the manufacture of pharmaceuticals have ail-inhibitory effect on the pressorlactionot 'epin'e'phrine whereas others may be useful in the preparation of other useful organic compounds.

The compounds of the present invention may ,be prepared by heating an aromatic acyl acetermine fwith"a "3 ca'rbo'n impo nd capame of forming a pyrite; iie' in a substantially 'a'nhyamus nea, organ c: liquid at a temperature of from 75"to 5106115150 C, for from about 1 hour to about. .,2Q .hours. Theproduct may be recovered by removal of the solvent, and is then purified by recrystallization.

The intermediate, aromatic acyl acetamidine compounds may be illustrated by the general formula in which R is an aryl radical. The aryl radical R may contain substituent radicals such as chlorine, bromine, methyl, methoxy, nitro, carbethoxy, and the like. These compounds are new and form the subject matter of our copending application, Serial Number 2,547, filed January 15, 1948. The preparation of a representative compound of this group is described in the specific examples hereinafter.

The 3 carbon compounds capable of forming a pyrimidine ring may include such compounds as beta-ethoxyacrolein diethyl acetal, beta-methoxyacrolein dimethyl acetal, beta-ethoxyacrolein dimethyl acetal, beta-methoxyacrolein diethyl acetal, beta-ethoxyacrolein dipropyl acetal,

.l fr a .e e i acetate, ethyl" actoac l e. T eact n.' ib ere a l ii on u em "p p d. tu a'n a. glacial acetic acid; etc., or

tate, propyl 'aeetoacetate,

'drous organic solvents as z Xtures thereofij w H erably under reflux conditions. The reaction may be conducted below the boiling point of the solvent 'or mixtureof solvents; however,. the time .req'uired;to cdmplete'the reaction atthe lower temperature is, of cours'ejlonger.

.The invention will now be illustratedin'greater particularity by means ofthe following'examples 'in which .1 representative 'Z phe'nacyIpyrimi'dines are prepared by the methoddescrib ed herei'ribe- 'foie. Theseexami les areillu'strat'iyeand not intended 'to restrict the invention to" the particular products or reaction conditions specifically described. All parts are by 'weighturfless otherwise indicated.

H rtamiize'z To ten grams 'of bnzdylacetonitrilefdissolyed in 50 ml. of dry benzene is added 12.; crabshanol.-.. b .-.mix re s. c m dic 0 and dry hydrogenchloride gas bubbled in until saturated. It is kept at OYCQ'overnight and then allowed to warm to roomtemperature, at which time only a.smal1 amountiof Crystalline" material is present in the liquor. j'Aft'er two hours at room temperature, the mixture is practically solid. The solid is filtered off, washed with benzene, and dried in the vacuum desiccator. It is then mixed with 50 ml. of alcoholic ammonia, which has been saturated with ammonia at 0 C. After standing for three days at room temperature, the mixture is filtered from the ammonium chloride. The alcohol is distilled off, and diethyl ether added to the syrupy residue, resulting in the precipitation of 7 g. of benzoylacetamidine. After two recrystallizationsfrom water the substance melts at 188-189 C.

A mixture of 16 g. benzoylacetamidine, 19.52 ml. beta-ethoxyacrolein acetal, 38 ml. amyl alcohol (B. P. 124-128 C. from Pentasol) and 10 ml. glacial acetic acid is refluxed for 10 hours, and the major portion of the solvents then distilled off at atmospheric pressure. Upon cooling the residue, 10 g. of solid crystallizes. An additional 2.1 g. is obtained from the mother liquors. Recrystallization of the product from isopropyl acetate yields 7.2 g. of 2-phenacylpyrimidine, a ye]. low solid melting at 147.8-148.5 C.

Example 2 To 1 g. of 2-phenacylpyrimidine in ml. of glacial acetic acid is added dropwise a solution of 0.808 g. of bromine in glacial acetic acid at 20 C. The mixture is drowned in water, resulting in the precipitation of a yellow solid. On recrystallization from ethanol 5-bromo-Z-phenacylpyrimidine is obtained which melts at 144.8-145.6 C.

Example 3 A mixture of g. of benzoylacetamidine, 6.2 g. of acetylacetone, cc. of mixed amyl alcohols and 6 cc. of glacial acetic acid is heated to refluxing for 12 hours. The solvents are distilled off under vacuum, and the syrupy residue washed with dilute sodium hydroxide and cold water, after which it slowly crystallizes. Approximately 12.5 g. of crude Z-phenacyl-4,6-dimethylpyrimidine is obtained. This may be purified in the form of its hydrochloride salt by dissolving in warm dilute hydrochloric acid, from which a yellow salt precipitates on cooling. The hydrochloride may be recrystallized from dilute acid or ethanol, and melts at 202-210 C. after two recrystallizations from the latter solvent. Upon dissolving the purified hydrochloride in water and adding sodium hydroxide, the base precipitates as a light yellow solid, which melts at 74- 75.5 C.

Example 4 A mixture of 3 g. benzoylacetamidine, 2.1 cc. ethylacetoacetate. 6 cc. of mixed amyl alcohols and 2 cc. of acetic acid is refluxed for 11 hours.

The solvents are distilled oifunder vacuum, and p in which R is a mono-cyclic aryl radical and R is a Z-pyrimidyl radical.

2. Z-phenacylpyrimidine.

3. 5-bromo-2-phenacylpyrimidine.

4. 2-phenacyl-4-methy1-6-hydroxypyrimidine.

5. A method of preparing compounds having the general formula:

in which R is a mono-cyclic aryl radical which comprises heating together in an inert anhydrous organic liquid an aroyl acetamidine and a betaalkoxyacrolein acetal, and thereafter recovering the said 2-aroyl methylene-pyrimidine.

6. A method of preparing compounds having the general formula:

C CHT 3X inwhich X is a halogen radical which comprises heating in an inert anhydrous organic liquid benzoylacetamidine and a beta-alkoxyacrolein acetal, halogenating the resulting 2-phenacylpyrimidine to obtain a 5-halo-2-phenacylpyrimidine and thereafter recovering said 5-halo-2- phenacylpyrimidine.

7. A method of preparing 2-phenacylpyrimidine which comprises heating in an inert anhydrous organic liquid benzoylacetamidine and beta-ethoxyacrolein diethyl acetal and recovering said Z-phenacylpyrimidine.

8. A method of preparing 5-bromo-2-phenacylpyrimidine which comprises heating benzoylacetamidine and beta-ethoxyacrolein diethyl acetal in an inert anhydrous organic liquid, brominating the reaction product and recovering said 5-bromo-2-phenacylpyrimidine.

9. A method of preparing Z-phenacyll-methyl-fi-hydroxypyrimidine which comprises heating in an inert anhydrous organic liquid benzoylacetamidine and ethyl acetoacetate and recovering said 2-phenacy1-4-methy1-6-hydroxypyrimidine.

10. Compounds having the general formula:

in which R is a mono-cyclic aryl radical and R" is a mono-halogenated Z-pyrimidyl radical.

JAMES M. SMITH, JR. BARBARA ROTH.

No references cited. 

